Treatment of ocular disorders

ABSTRACT

The present invention is in particular related to the use of rivastigmine in the manufacture of a medicament for the treatment of ocular disorders.

This invention is in particular related to the use of rivastigmine inthe manufacture of a medicament for the treatment of ocular disordersselected from glaucoma and neurodegenerative disease conditions of theretina and the optic nerve.

The term glaucoma includes symptoms of the eye which are especially tobe attributed to increased intraocular pressure. Frequently, anobstruction to drainage of the aqueous humour leads to an increase inthe intraocular pressure. Chronically raised intraocular pressure has aharmful effect on the optic nerve and the retina, which can terminallylead to blindness. Accordingly, for the treatment of glaucoma, activeingredients are used which are typically able to reduce the intraocularpressure (IOP). For example, increased IOP be treated with certainβ-adrenoceptor blockers.

More recently, the phenomenon of so-called normal tension glaucoma (“lowtension” or “normal tension glaucoma” is used synonymously) has now beenclinically established in ophthalmology [J. Flammer, Fortschr.Ophthalmol. 87, 187(1990)]. Normal tension glaucoma is characterized byan intraocular pressure which is typically in the normal range, i.e. isnot increased, but in which the optic disc (papilla nervi optici) ispathologically excavated and the field of vision is impaired. Thepathogenetic factors are especially circulatory problems in the ocularblood vessels, which may be caused e.g. by atherosclerosis, hypotension,orthostasis, functional vasospasms and neurodegenerative factors.

It has now surprisingly been found that rivastigmine, its racemate, itsanalogs and/or its pharmaceutically acceptable salts are highlyeffective in the treatment of glaucoma and disorders of neurologicalpathogenesis (neurodegeneration), such as normal tension glaucoma.

Accordingly, a first aspect of the present invention is related to theuse of a compound of formula (I),

wherein

R1 is hydrogen, lower alkyl, cyclohexyl, allyl or benzyl,

R2 is hydrogen, methyl, ethyl or propyl or

R1 and R2 together with the nitrogen to which they are attached form amorpholino or piperidino radical,

R3 is hydrogen or lower alkyl,

R4 and R5 are the same or different and each is a lower alkyl, and thedialkylaminoalkyl group is in the meta, ortho or para position,

in free base or pharmaceutically acceptable acid addition salt form,

in the preparation of a pharmaceutical composition for the treatment ofan ocular disorder selected from the group consisting of glaucoma,normal tension glaucoma and neurodegenerative disease conditions of theretina and the optic nerve.

In a preferred embodiment the dialkylaminoalkyl group is in the metaposition.

A more preferred compound in accordance to formula (I) is racemicN-ethyl-3-[(1-diethylamino)-ethyl]-N-methyl-phenyl-carbamate free baseand/or acid addition salt.

An even more preferred compound in accordance to formula (I) is(S)-N-ethyl-3-[(1-diethylamino)-ethyl]-N-methyl-phenyl-carbamate freebase and/or acid addition salt.

A preferred acid addition salt is derived from tartraric acid.

A highly preferred compound in accordance to formula (II) is(S)-N-ethyl-3-[(1-diethylamino)-ethyl]-N-methyl-phenyl-carbamatehydrogen tartrate (rivastigmine).

This invention is preferably related to the treatment of normal tensionglaucoma and neurodegenerative disease conditions of the retina and theoptic nerve, and even more preferred to neurodegenerative diseaseconditions of the retina and the optic nerve.

A further aspect of the present invention is a method of treating anocular disorder, which disorder is selected from the group consisting ofglaucoma, normal tension glaucoma and neurodegenerative diseaseconditions of the retina and the optic nerve, which method comprises therepeated administration of a pharmaceutically effective amount of acompound of formula (I), to an individual in need of such treatment,

wherein

R1 is hydrogen, lower alkyl, cyclohexyl, allyl or benzyl,

R2 is hydrogen, methyl, ethyl or propyl or

R1 and R2 together with the nitrogen to which they are attached form amorpholino or piperidino radical,

R3 is hydrogen or lower alkyl,

R4 and R5 are the same or different and each is a lower alkyl, and thedialkylaminoalkyl group is in the meta, ortho or para position,

in free base or pharmaceutically acceptable acid addition salt form.

A preferred mode of administering a compound of the present invention isthe topical, and more preferably the topical ocular administration.

A preferred group of individuals are human beings.

The term repeated administration refers in particular a weekly and morepreferably to a daily administration, wherein the active is administeredin regular intervals from one to ten times, more preferably from one tosix times, and even more preferably from one to three times.

For the purposes of the present invention, the term “lower” inconnection with radicals and compounds, unless defined otherwise,denotes, in particular, radicals or compounds having up to 8 carbonatoms, preferably up to 4 carbon atoms.

Accordingly, lower alkyl has up to 8 carbon atoms, and can bestraight-chain or branched, preferably up to 4 carbon atoms, and is, forexample; methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,tert-butyl, pentyl, hexyl or isohexyl.

Alkyl has up to 18 carbon atoms and can be straight-chain or branched.Suitable examples are octadecyl, undecyl, octyl, hexyl, pentyl, butyl,propyl, ethyl, and the like.

MATERIALS AND METHODS

1. Animals

Male and female adult brown burgundy rabbits (2.6-4.4 kg) are used inthis study. Animals are kept in individual cages under well-defined andstandardized conditions (humidity and temperature controlled room, 13 hlight/11 h dark cycle) with standard dry food and water adlibitum. Allanimals are accustomed to the procedure of IOP measurement by only thoseanimals that have stable records are included in the study. Allexperiments are conducted in accordance with the ARVO resolution for theuse of animals in ophthalmic and vision research and are approved by theFederal and Local Ethical and Agricultural Committees.

2. Drugs

Compounds in accordance to formula (I) indicated above and in particular(S)-Nethyl-3-[(1 -diethylamino)-ethyl]-N-methyl-phenyl-carbamate.

Topical anaesthesia of the cornea is induced with Novocaine 0.2%(Inselspital Pharmacy) eye drops.

Solutions of a test drug are freshly prepared before each experiment bydissolution in sterile balanced salt solution (BSS) (AlconPharmaceuticals Ltd, Forth Worth, Tex., USA) at the requiredconcentrations under sterile conditions. One 50-μL drop of the testsolution is applied topically to the right eye whereas the contralateraleye receives the carrier BSS only.

3. IOP Measurements

IOP is measured with a TonoPen XL (Mentor, Norvel, Mass.), the devicebeing calibrated daily according to the manufacturer's instructions. Thefirst measurement result with a coefficient of variation displayed <5%is noted. Less than 5% of the measurements are repeated until thecoefficient of variation displayed is <5%. Corneas are anaesthetized bytopical application of a 50-μL drop of 0,2% Novocaine prior to each IOPmeasurement.

Measurements are always initiated at the same time (8 a.m.), asufficient recovery period of at least 7 days is provided for theanimals between the experiments. Control readings are taken 10 minutesbefore instillation of the test drug to the right eye and of the vehicleto the left one. IOP is recorded at 1-hour intervals for the ensuing 8hours. Baseline measurements are likewise performed hourly in allanimals prior to treatment, for monitoring of diurnal rhythms. (9)

4. Pupil Diameter

Pupil diameter is measured horizontally in both eyes using a pupil gaugeclosely applied to the cornea under diffuse illumination conditions.

5. Slit-Lamp Examination

Slit-lamp biomicroscopy is performed by a trained ophthalmologist beforedrug administration and 4 and 8 hours thereafter. Eyes are controlledfor conjunctival redness and discharge, for integrity of the cornealepithelium and for the absence or presence of flare (protein in theanterior chamber being an indication of blood aqueous barrierbreakdown).

6. Statistical Analysis

Data are analyzed according to the Mann-Whitney U-test. IOP valuesrecorded before and after application of Rivastigmine or the drugvehicle are compared in the same eye, differences with a first ordererror of P<0.05 being considered as statistically significant.

Results

Rivastigmine lowers the IOP significantly in the treated eye. Maximalmean decreases in IOP are time-staggered according to the concentrationof the drug solution used, occurring 1, 3, and 5 hours after applicationof 5% (3.5±1.2 mm Hg), 2% (2.2±0.8 mm Hg), and 1% rivastigmine (2.6±1.2mm Hg), respectively. After administration of the 1% rivastigminesolution the longest significant IOP-lowering effect is observed during5 hours in the treated eyes (Table 1A). In untreated eyes, maximal meandecreases in IOP are likewise time-staggered, occurring 1, 3, and 4hours after application of 5%, 2%, and 1% rivastigmine, respectively, tothe contralateral ones. However, only the effect induced by 5%rivastigmine is significant (Table 1 B). Overall, in the treated anduntreated eyes, the maximal IOP decrease occurs 1 hour afteradministration of the 5% drug solution.

An insignificant miotic pupil reaction is observed in some drug-treatedeyes. No signs of rivastigmine-related local toxicity are manifested.

TABLE 1A Right eye data (treated) Time (hrs) 0 1 2 3 4 5 6 7 8 IOP (mm)Control 12.1 13.8 14.0 12.3 12.3 13.0 12.9 11.5 13.0 1% Rivastigmine12.3 12.0 11.2 10.8 10.5 10.1 11.1 11.5 11.6 2% Rivastigmine 11.5 11.511.0  9.2 10.8 11.5 11.1 10.8 12.0 5% Rivastigmine 13.7 10.0 11.1 10.810.5 12.9 12.5 14.0 11.8

TABLE 1B Left eye data (untreated) Time (hrs) 0 1 2 3 4 5 6 7 8 IOP (mm)Control 12.2 13.4 13.2 12.0 12.8 13.9 13.5 12.1 14.0 1% Rivastigmine12.0 11.6 11.2 11.1 10.2 11.0 10.7 11.1 11.4 2% Rivastigmine 11.2 11.911.2 10.2 12.3 11.5 11.2 11.0 13.0 5% Rivastigmine 13.4 10.7 11.5 11.311.9 13.2 12.5 13.3 13.0

The above tables 1A and 1B exhibit baseline measurements (positive SD)and mean IOP measurements recorded after topical application of a single50-μL drop of 1% (n=8) (negative SD), 2% (n=4) and 5% (n=6) rivastigmineto the right eyes (A), and of a similar volume of the drug vehicle tothe left ones (B), of normotensive adult rabbits. In the drug-treatedgroup, maximal effects occur after 1 hour (5% rivastigmine), 3 hours (2%rivastigmine) and 5 hours (1% rivastigmine). In the untreated eyes,maximal IOP-reductions occur 1,3 and 4 hours after administration of 5%,2% and 1% rivastigmine, respectively, to the partner ones. (**P<0.05)

The neuroprotective effect of rivastigmine—after topical application—inaddition to its well-tolerated ocular hypotensive effect makes it acompound of choice for the treatment of normotensive glaucoma.

What is claimed is:
 1. A method of decreasing intraocular pressure in asubject in need of such treatment comprising: repeatedly topicallyadministering to the eye of a subject in need of treatment an amounteffective to decrease intraocular pressure in said eye of said subjectof a compound with the formula

 wherein R1 is hydrogen, lower alkyl, cyclohexyl, allyl, or benzyl; R2is hydrogen, methyl, ethyl, or propyl; or wherein R1 and R2 togetherwith the nitrogen to which they are attached form a morpholino orpiperidino radical; R3 is hydrogen or lower alkyl; R4 and R5 are,independently, lower alkyl;  wherein the

 group is in the meta, ortho, or para position relative to the carbamategroup; or a pharmaceutically acceptable acid addition salt thereof. 2.The method of claim 1 wherein the

group is in the meta position relative to the carbamate group.
 3. Themethod of claim 1, wherein the compound is racemicN-ethyl-N-methyl-3-[(1-dimethylamino)ethyl]-phenyl carbamate free baseor an acid addition salt thereof.
 4. The method of claim 1, wherein thecompound is (S)-N-ethyl-N-methyl-3-[(1-dimethylamino)ethyl]-phenylcarbamate free base or an acid addition salt thereof.
 5. The method ofclaim 1, wherein the compound is(S)-N-ethyl-N-methyl-3-[(1-dimethylamino)ethyl]-phenyl carbamatehydrogen (2R,3R)-tartrate.